This application relates to the treatment of prostate tumors making use of an antisense oligonucleotide that has a sequence complementary to the sequence encoding insulin-like growth factor binding protein (IGFBP)-2.
Prostate cancer is the most common cancer that affects men, and the second leading cause of cancer death in men in the Western world. Because prostate cancer is an androgen-sensitive tumor, androgen withdrawal, for example via castration, is utilized in some therapeutic regimens for patients with advanced prostate cancer. Androgen withdrawal leads to extensive apoptosis in the prostate tumor, and hence to a regression of the disease. However, castration-induced apoptosis is not complete, and a progression of surviving tumor cells to androgen-independence ultimately occurs. This progression is the main obstacle to improving survival and quality of life, and efforts have therefore been made to target androgen-independent cells. These efforts have focused on non-hormonal therapies targeted against androgen-independent tumor cells; however, no non-hormonal agent has improved survival thus far (Oh et al., J. Urol 160: 1220–1229 (1998)). Alternative approaches are therefore indicated. Recent studies in our laboratory suggest that increased levels of IGFBP-5 (Miyake et al, Endocrinology 141:2257–2265, (2000)) and IGFBP-2 after androgen ablation enhance IGF-1 mitogenesis and cell survival, thereby accelerating progression to androgen ablation.
Insulin-like growth factor (IGF)-I and IGF-II are potent mitogens for many normal and malignant cells. Accumulating evidence suggests that IGFs play an important role in the pathophysiology of prostatic disease and breast cancer (Boudon et al., J. Clin. Endocrin. Metab. 81: 612–617 (1996); Angelloz-Nicoud et al., Endocrinology 136: 5485–5492 (1995); Nickerson et al., Endocrinology 139: 807–810 (1998); Figueroa et al., J. Urol. 159: 1379–1383 (1998)).
The biological response to IGF's is regulated by various factors, including IGFBPs. To date, six IGFBPs have been identified whose function is believed to involve modulation of the biological actions of the IGFs through high affinity interactions (Rajaram et al. Endocrin. Rev. 18: 801–813 (1997)). However, some evidence suggests biological activity for IGFBPs that are independent of IGPs (Andress et al., J. Biol. Chem. 267: 22467–22472 (1992); Oh et al., J. Biol. Chem. 268: 14964–14971 (1993)), and both stimulatory and inhibitory effects of IGFBPs on cell proliferation have been reported under various experimental conditions (Andress et al., supra; Elgin et al., Proc. Nat'l. Acad. Sci. (USA), 84: 3254–3258 (1987); Huynh et al., J. Biol. Chem. 271: 1016–1021 (1996); Damon et al., Endocrinology 139: 3456–3464 (1998)). Thus, the precise function of IGFBPs remains controversial. Because of this, while the reported results implicate IGF in prostate cancer, they do not clearly suggest a therapeutic approach based upon this involvement.
The present invention utilizes antisense oligodeoxynucleotides (ODNs) targeted to IGFBP-2 as a treatment for prostate and other endocrine cancers. Antisense ODNs are stretches of single-stranded DNA that are complementary to mRNA regions of a target gene, and thereby effectively inhibit gene expression by forming RNA/DNA duplexes (Figueroa et al., J. Urol., 159: 1379–1383 (1998)). Phosphorothioate ODNs are stabilized to resist nuclease digestion by substituting one of the nonbridging phosphoryl oxygens of DNA with a sulfur. Recently, several antisense ODNs specifically targeted against genes involved in neoplastic progression have been evaluated both in vitro and in vivo, and demonstrated the efficacy of antisense strategy as potential therapeutic agents (Monia et al., Nature Med. 2: 668–675 (1996); Cucco et al., Cancer Res. 56: 4332–4337 (1996); Ziegler et al., J. Natl. Cancer Inst. 89: 1027–1036 (1997); Jansen et al., Nature Med. 4: 232–234 (1998)).